This is a resubmission of grant proposal R01 HL091880-01, "Restless Legs Syndrome, Cardiovascular Risk Factors, and Cardiovascular Disease." This proposal has three specific aims: 1) to evaluate the association between restless legs syndrome (RLS) and prevalent risk factors for cardiovascular disease (CVD);2) to evaluate the association between RLS and prevalent overall and specific types of CVD;and 3) to evaluate the association between RLS and incident overall and specific types of CVD. RLS is a common neurological disorder characterized by unpleasant sensations of the legs and an urge to move them for relief. Because symptoms are intensified by inactivity and lying down, RLS patients are often sleep deprived, exhausted and fatigued. Occupational performance, social activities, and family life are severely impaired. Most prevalence estimates indicate that between 7% and 10% of the population suffers from RLS, although with different symptom frequencies. However, RLS is probably underdiagnosed. Despite the publication of the so-called minimal criteria for RLS in 1995 and their 2003 revision, which accelerated epidemiologic RLS research, still little is known about the onset and course of the disease and its consequences on a population level. Recently, it has been suggested that RLS is associated with a more unfavorable cardiovascular risk factor profile, including higher prevalences of smoking, hypertension, nocturnal blood pressure changes, and diabetes. Since these observations were made in cross-sectional studies, it is, however, unclear whether RLS is a cause or a consequence of an unfavorable risk factor profile. All of these CVD factors increase the risk of subsequent CVD events. Thus, it is plausible that RLS is not only associated with risk factors for CVD but also with subsequent CVD events. We propose to study these questions in three large-scale, well-characterized, prospective cohort studies of over 20,000 men (Physicians'Health Study I and II) and 33,000 women (Women's Health Study) with over 21, 9, and 12 years of follow-up, respectively. In all three studies, the minimal diagnostic criteria of the International RLS Study Group to ascertain RLS in epidemiologic studies were included in self-administered questionnaires. Since all studies were originally designed as primary prevention trials of CVD and cancer, information about these outcomes is excellent, and all events were confirmed by medical record review. Furthermore, all participants provided high-quality information about a large number of lifestyle habits, diet, medical history, and personal characteristics at baseline and during follow- up. Thus, these three prospective cohort studies of men and women provide a unique opportunity to study the interrelationships between RLS, risk factors for CVD, and CVD events. Since most information has already been collected and ongoing data collection is imbedded in ongoing NIH funded projects, we can propose to study these questions in a very cost-effective way. PUBLIC HEALTH RELEVANCE: About 10% of the population suffers from Restless Legs Syndrome (RLS), a neurological disorder characterized by unpleasant sensations of the legs and an urge to move them for relief. Recently, it has been suggested that RLS is associated with a more unfavorable risk profile for cardiovascular disease (CVD). Thus, the question arises as whether patients with RLS have not only a higher prevalence of CVD risk factors but whether they are also at increased risk for subsequent CVD events. Thus, this grant proposal request funding to study the association between RLS, CVD risk factors as well as CVD events.